- AGTR1 encodes for the Angiotensin-II receptor type 1 enzyme
- The CC genotype was also more prone to high blood pressure from a high fat – especially with excessive carbohydrates – diet
- The NF-kb pathway is a downstream target of AGTR1
> This means that elevated ACE1 and the upregulation of AGTR1 combined puts the body in an inflammatory state, allowing a virus to thrive

- Nitric oxide downregulates AGTR1, balancing out the variant upregulation and blood pressure
- To do this, include nitric oxide precursors like L-arginine, folate, vitamin C, magnesium, vitamin D, DHA, and leafy green vegetables.

Michigan State University

SUMMARY OF CURRENT INFO
- Research for ACE1
- Research for AGTR1
- Research for ACE2
- Research for TMPRSS2 and ESR2
- Nutritional strategies

ARTICLES
- Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework

Nutrigenomics

https://nutritiongenome.com/the-latest-nutrigenomic-research-on-covid-19/

The Latest Nutrigenomic Research on COVID-19

-The ACE1 rs4343 gene is characterized by a genetic deletion/insertion (D/I) polymorphism and is associated with approximately 60% of circulating and tissue concentrations of ACE
- The GG genotype is associated with a higher baseline of the ACE1 enzyme in serum, AG intermediate, and AA low ACE1
- **High ACE1 leads to low ACE2**

- In a twins study, after six weeks of a high saturated fat diet over 37%, circulating ACE concentrations increased by 15%, accompanied by an increased ACE gene expression in adipose tissue.
- **The homozygous carriers (GG) of the variant had higher baseline ACE concentrations and additionally showed a 2-fold increase in ACE concentrations in response to the high saturated fat diet as compared to the AA and AG genotype**
- GG carriers also responded with higher systolic blood pressure as compared to AA and AG carriers

- Women have naturally lower levels of ACE1, and men may have a higher probability of ACE1 expressing higher
- The ACE1/ACE2 imbalance during ACE2 receptor suppression in the presence of SARS-CoV-2 infection is more likely in men and may help explain the differences in severity based on sex

ACE1 inhibition has been demonstrated in research by bilberry, grapes, allicin (raw garlic), cinnamon, and jasmine.

Research for ACE1

Research for AGTR1

- The expression of ACE2 has been detected in nasal epithelial cells, alveolar epithelial type II cells of lungs, and the luminal surface of intestinal epithelial cells
- The nose, lungs, and intestine facilitate viral entry and serve as a potential site of viral invasion
- However, it appears the expression of TMPRSS2 determines the ability of the virus to enter the cells

- Research has suggested that age, sex, and genetic variants in the ACE2 gene can potentially affect ACE2 levels in the body
- Children generally have higher levels of ACE2 than adults. Women have been found to have higher ACE2 levels than men due to the upregulation of ACE2 by estrogen
- This could be the foundational reason men and post-menopausal women are more susceptible to COVID-19

- One study of 534 subjects found that 67% of the variation in circulating ACE2 could be accounted for by genetic factors. Among different polymorphisms, it has been speculated that ACE2 rs2106809 might exhibit primary effects on the ACE2 levels. The circulating ACE2 levels tend to be greater in AA or AG genotype compared with that in the GG genotype.

- How do you increase ACE2 expression? Potassium, vitamin D, and resveratrol. What was interesting about resveratrol is that it mitigated the effect of a high-fat diet by increasing the expression of ACE2 in animal studies. Betulinic acid (chaga mushroom) and oleanolic acid (olive oil) have also been studied as SARS-CoV-2 entry inhibitors.

Research for ACE2

- TMPRSS2 expression is several times higher in the prostate compared with any other tissue, as well as the upper digestive and respiratory tract.
- ESR2 is also found in the prostate, lungs, breast, and the cardiovascular system with implications in blood clotting. TMPRSS2 acts like the shape of the keyhole, while ACE2 is the actual lock. A higher expression of TMPRSS2 means a better keyhole fit for viruses
- In a study looking at the Italian population, expression levels of both ACE2 and TMPRSS2 were assessed. Researchers found no significant evidence that ACE2 is associated with COVID-19 severity or sex bias in the Italian population
> However, TMPRSS2 levels and genetic variants proved to be possible candidate disease modulators, contributing to the observed epidemiological data among Italian patients. Genes related to higher levels of TMPRSS2 were more frequent in Italians vs. East Asian populations.
- Research has found that the expression of the fusion gene TMPRSS2:ERG, which is thought to be responsible for up to 80% of prostate cancers, is repressed by estrogen receptor beta (ESR2 gene) agonists. Phytoestrogens are agonists known to have up to 30-fold greater affinity for estrogen receptor beta.

DECREASING THE EXPRESSION OF TMPRSS2
-  Phytoestrogens, curcumin, and lycopene (tomato sauce)
- Research has shown that curcumin binds to receptor-binding domain site of viral S protein and also to the viral attachment sites of ACE2 receptor and downregulates TMPRSS2, demonstrating that curcumin can act as potential inhibitory agent antagonizing the entry of SARS-CoV2 viral protein.
> Variants in the ESR2 gene increase the need for phytoestrogens for prostate and breast health. Post-menopausal women will also benefit from increasing phytoestrogen intake.

Research for TMPRSS2 and ESR2

- Balance ACE1/ACE2 with appropriate fat intake based on gene results, making sure vitamin D is in range, increasing potassium intake from plants, and foods high in resveratrol.
> Foods that have demonstrated ACE1 inhibition including bilberry, grapes, raw garlic, cinnamon, and jasmine.
- For those with variants in ESR2 and the TMPRSS2 gene, and post-menopausal women, increase phytoestrogen, turmeric, and lycopene (tomato sauce) intake
- The best phytoestrogens in research for blood pressure and the ESR2 gene include dark berries (contains resveratrol), beans, rye, hummus, peanuts (contains resveratrol), miso soup, flax seeds (women), tahini sauce, and cruciferous vegetables (broccoli, cabbage, kale, Brussels sprouts)
- Higher levels of TMPRSS2 have been found to upregulate and activate NF-kb creating an inflammatory environment. NF-Kb inhibitors can be both preventative for inflammation and successful with slowing viral aggressiveness.
> These include vitamin C, vitamin D, zinc, selenium, magnesium, resveratrol (red wine, peanuts, pistachios, blueberries, bilberries, cranberries, cacao, and muscadine grapes), triterpenoids (Chaga, reishi, olive oil, holy basil), caffeic acid (coffee, Chaga, red wine, elderberry), and anthocyanins (elderberry, gogi berries, cacao).
- Zinc and copper should be at a 15mg to 1mg balance. A balanced diet of animal and plant foods typically hit this ratio.
> A plant-based diet may be low in zinc and high in copper and can cause sodium cravings.
> High iron levels, malabsorption syndromes, and high amounts of supplemental zinc without copper can push copper too low.
> Copper deficiency can enhance the vulnerability of the heart and blood vessels to damage.

Nutritional Strategies

- The optimal status of specific nutrients is considered crucial to keeping immune components within their normal activity, helping to avoid and overcome infections
- Specifically, the European Food Safety Authority (EFSA) evaluated and deems six vitamins (D, A, C, Folate, B6, B12) and four minerals (zinc, iron, copper and selenium) to be essential for the normal functioning of the immune system
- an update on the evidence of the contribution of nutritional factors as immune-enhancing aspects, factors that could reduce their bioavailability, and the role of the optimal status of these nutrients within the COVID-19 pandemic context was carried out
- Results from the review approach show the importance of maintaining a correct nutritional status of these 10 nutrients analyzed for the health of the immune system, highlighting the importance of Vitamin D and iron in the context of COVID-19
- the ecological study demonstrates that intake levels of relevant micronutrients-especially Vitamins D, C, B12, and iron-are inversely associated with higher COVID-19 incidence and/or mortality, particularly in populations genetically predisposed to show lower micronutrient status
- Overall, nutrigenetic data provided by joint assessment of 10 essential nutrients for the functioning of the immune system and of the genetic factors that can limit their bioavailability can be a fundamental tool to help strengthen the immune system of individuals and prepare populations to fight against infectious diseases such as COVID-19

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